Only the ionized magnesium is biologically active yet this represents only about 3% of the total body magnesium. However, the ionized magnesium concentration would be a more accurate estimate of magnesium status and its relationship to disease processes. We evaluated two technologies for the determination of ionized magnesium; ion-selective electrodes for ionized magnesium in serum and nuclear magnetic resonance spectroscopy (NMRS) for tissue. We found a lack of correlation for results for ionized magnesium between two different ion-selective electrodes with specimens from normal volunteers and patients. On the other hand, results with NMRS determination of ionized magnesium in muscle and brain were consistent with other reports using this technology and also other techniques for these two tissues. We determined ionized magnesium in muscle by NMRS and blood serum, red blood cell and mononuclear blood cell total magnesium concentrations across the menstrual cycle in normal women. We found no significant differences for these estimates of magnesium across the menstrual cycle. Patients treated with interleukin-2 (lL-2) for malignancy show a precipitous drop of the serum magnesium concentration within 24 to 48 hours of beginning therapy. Previous studies showed that essentially no magnesium I excreted in the urine. We determined the blood magnesium parameters (serum total and ionized, total red blood cell, and total mononuclear blood cells) and white cell count and differential every 12 hours during lL-2 therapy. The results show that the significant leukopoiesis that occurs with lL-2 therapy apparently takes magnesium from the serum to the bone marrow for the production of these cells. This study elucidates the mechanism of magnesium deficiency (as defined by the total serum magnesium concentration) for lL-2 therapy.